Alcohol consumption is a major etiology of chronic liver disease worldwide. The morphological spectrum of human alcoholic liver disease includes fatty liver, alcoholic hepatitis, and cirrhosis. In rodents, intragastric infusion of ethanol for 4-5 weeks leads to steatosis, inflammation, and to a less extent fibrosis in the liver, whereas feeding Lieber-DeCarli liquid diet containing ethanol does not cause significant liver injury except steatosis. In humans, interestingly, only a small percentage of heavy drinkers (10-15%) developed alcoholic liver injury, strongly suggesting that alcohol is a cofactor for developing chronic liver disease. Accumulating evidence suggests that many genetic and acquired factors are implicated in the susceptibility of the individual to alcohol-induced liver injury. It has been well documented that alcohol consumption accelerates the development and progression of liver disease induced by hepatitis virus infection. Our lab is to study how chronic ethanol consumption potentiates liver injury induced by other toxins or viruses and to study the molecular mechanisms underlying alcohol-induced liver injury. We have demonstrated that IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. Our findings also showed that treatment with IL-6 ameliorates fatty liver disease in alcohol-fed mice, high-fat?diet fed mice, and genetically modified ob/ob mice. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). Currently, we are exploring the molecular mechanisms underlying the protective effect of IL-6 in fatty liver disease by using STAT3 conditional knock out mice.[unreadable] [unreadable] In addition, we are also collaborating with Dr. George Kunos from NIAAA to investigate the role of canabinoid in alcoholic liver disease, and with Dr. Jake Liang from NIDDK to study the interaction of alcohol and hepatitis viral proteins in liver injury.